SDF-1 is the only receptor for the CXCR4 HIV chemokine coreceptor utilized by pathogenic X4 HIV-1 strains for cell entry. SDF1-3'A is a mutation in an evolutionarily conserved region of the 3'untranslated region (UTR). Our working hypothesis has been that the SDF1-3'A mutation stabilizes the mRNA and thus increases the amount of transcript available for translation. This may result in an increase of SDF-1 available for binding to CXCR4 and a downregulation of surface CXCR4 expression. Careful sequencing of the 5'UTR and the open reading frame has not revealed any other polymorphisms in linkage disequilibrium with SDF1-3'A or associated with rate of disease progression. SDF1-3'A , which appears to recessively protect individuals from developing AIDS in the first decade after infection in our cohorts, has been associated with an increased dominant risk for developing non-Hodgkin's lymphoma in a study of HIV-1-infected hemophiliacs, homosexuals, and infants. We have performed a categorical analysis comparing allele and genotype frequencies between HIV seropositive cases with non-Hodgkin's lymphoma and controls matched for duration of HIV-1 infection and CD4 T-cell number and have been unable to detect significant differences in allele or genotype frequencies between cases and controls. In collaborative studies, a sensitive assay for determining serum SDF-1 concentrations has been developed to quantify SDF-1 in normal and HIV-infected donors. Our collaborator has shown that SDF-1 is elevated in HIV-1-infected persons relative to normal controls. We are now investigating: 1) if this difference is due to SDF-1 genotypes; 2) if the SDF-1 elevation in HIV-1 patients is related to a shift in HIV tropism or surface density of CXCR4 and/or CCR5 ; 3) if SDF-1 elevation seen in HIV patients is related to superimposing diseases like malignancies or infectious diseases; and 4) if SDF-1 elevation seen in HIV patients is related to therapeutic status and HIV-1 clinical outcomes. Very preliminary data show a trend of less surface CXCR4 on cells obtained from donors of the SDF1-3'A/SDF1-3'A genotypes compared to individuals carrying the wildtype allele. The SDF1 Gene and Progression to AIDS